Migraine is a painful syndrome characterized by unilateral, pulsating headaches, nausea, vomiting, and sensitivity to light and sound. Approximately 23 million Americans presently suffer from this disorder. Drugs that have been used in an attempt to treat migraine include: ergotamine and ergotamine-like agents; serotonin agonists; and caffeine with ergots or other pharmacologic agents (see e.g., Silberstein, S. D., Curr. Opinion Neurology 7:258–263 (1994); Welch, K. M. A., New Engl J. Med. 329:1476–1483 (1993); Kumar, K. L., J. Gen. Int. Med. 9:339–348 (1994); Saadah, H., Headache 32:95–97 (1992); and Becker, Arzneimittelforshung 42(4):552–555 (1992)). All of these drugs are thought to initially relieve migraine-associated pain by causing vasoconstriction. Unfortunately, this leads to numerous side effects such as chest pain or pressure, flushing, generalized tingling sensations, nausea, vomiting, pain in the legs and arms, asthenia, drowsiness, and dizziness. Acute ergotism is a particularly pernicious side effect of ergot drugs and is characterized by severe central and peripheral vasoconstriction, nausea, vomiting, diarrhea, colic, headache, vertigo, paresthesia, and possibly convulsive seizures.
Patients have, on occasion, found total or partial relief for some forms of migraine through the use of non-prescription analgesics. As outlined by Welch (New Engl J. Med. 329:1476–1483 (1993)), the initial dosages of such analgesics are typically: aspirin, 500–650 mg; acetaminophen, 500 mg; naproxen sodium, 750–825 mg; tolfenamic acid, 200–400 mg; and, ibuprofen 200 mg. After oral dosing, peak plasma concentrations in normal subjects usually occur at about 1 hour for aspirin and acetaminophen, and between 1 and 2 hours for naproxen sodium, tolfenamic acid, and ibuprofen. However, the absorption of these and other agents during a migraine attack has been shown to be impaired, apparently due to gastric stasis.
Ideally a migraine drug formulation should be nonaddictive and free of vasoactive agents (i.e. agents causing the constriction or dilation of blood vessels). This requires the exclusion of ergots, serotonin agonists such as sumatriptan (including related 5HT agonist heterocyclic compounds as described in U.S. Pat. No. 4,816,470) and caffeine. The formulation should relieve pain, reduce gastric stasis, reduce nausea, and allow for a faster rate of drug absorption.
Metoclopramide is a drug known to relieve migraine-associated nausea when administered at a minimum oral dose of 10 mg. Poyser et al. have described a formulation in which aspirin is uniformly intermixed with metoclopramide (U.S. Pat. No. 4,380,540). One drawback of this formulation is that it undergoes unacceptable degradation in a matter of two to three weeks at ambient temperatures. In addition, aspirin is known to have a very short plasma half life. New formulations of metoclopramide that are effective in treating migraine headache and that avoid the disadvantages of this and other previously disclosed preparations would represent a clear advance in the art.